There are many cells in the brain (109), which are wired to form specialized circuits. These circuits have many functions ranging from; perception, movement and memory. How the circuits perform their tasks is largely due to the type of receptors they posses, their morphological structure and who they are wired with. This complex wiring of neurones makes the brain the most complex organ however; the way it works can be simplified into two opposing forces; excitation and inhibition. Neurones which work via chemical synapses are excited by excitatory pyramidal cells using neurotransmitter glutamate and are inhibited by inhibitory interneurones releasing the neurotransmitter, GABA that acts on GABA receptors. Under or over activity of these 2 opposing forces have been implicated in neurodegenerative (e.g. epilepsy and Parkinson?s disease) and psychiatric diseases (e.g. anxiety and schizophrenia). The proposed research is to provide a better understanding of how the homeostatic balance of inhibition and excitation is achieved. 80% of cells in cortical regions consist of the pyramidal cell family while inhibitory interneurones consist of 6-7% of cells in cortical regions. Interneurones fall into different sub families, which are diverse in their morphology, neurochemistry, electrophysiological properties and the type of GABA receptors they posses. The interneurones make synapses with pyramidal cells and other interneurones to regulate and fine tune pyramidal cell activity, thus preventing over excitability of the network. This study is very important since not only will it provide valuable information on interneurone physiology, pharmacology and morphology but will also provide insight on neuronal subtypes which may be selectively affected in a particular disease states. The outcome of this research has direct relevance to human neuropathology, since it will allow us to design drugs to target specific pathways in the brain to treat neurological disorders, including depression and anxiety, which impact significantly on UK citizens, i.e. 1 in 4 adults may experience a mental health problem in any given year. Depression alone is thought to be the second most costly illness worldwide (Murray and Lopez, 1996) by year 2020, representing the biggest global economic health burden after heart disease. The treatment for such disorders include benzodiazepines, barbiturates, which act through GABAA neurotransmitter receptors, making the GABAA receptor a prime target for the development of new drugs and improved selectivity of existing ones.

Meningitis and sepsis remain devastating diseases, particularly in the young. If patients survive, there are usually serious consequences that include mental retardation, seizures, cerebral palsy and hearing loss. Antibiotic therapy may not always be effective because the infection progresses very rapidly and antibiotic resistant bacteria are now more commonly found. There is widespread recognition that new approaches to the treatment of the disease are urgently needed. These serious infections in the newborn infant and in older children are caused by a relatively small number of bacterial types and they are almost all protected from the effects of the patient?s immune system by a coat, or capsule, comprising linked sugar molecules. There is ample evidence that the capsule is essential for the survival of the bacteria within the tissues of the patient, as without it they are no longer able to protect themselves from immune attack. We are looking for ways to rapidly remove this protective layer as a novel way of treating the infection ? our approach, which we call phenotypic modification, does not rely on directly killing the bacteria in the way that most antibiotics do, but aims to convert them to a ?less fit? form that cannot survive in the body. We have found an enzyme, derived from a bacterial virus or ?bacteriophage?, which quickly and selectively strips the capsule from the bacterial surface and sensitises the pathogenic organisms to the body?s defences. We have used the enzyme to treat experimental infections in newborn rats and we find that injection of very small amounts of material can very effectively cure the animals of what is invariably a fatal infection. This is the first demonstration that we know of which shows that ?phenotypic modification? can work in whole animals. We now which to achieve a greater understanding of the nature of the infection in the animal model by studying the distribution of the pathogen in animal tissues and organs and we would also like to establish that the positive therapeutic outcome that we observe is really due to removal of the protective capsule at the site of infection. Finally, we propose to use ?microarray technology? to establish whether key rat gene products are involved in the determination of the therapeutic outcome.

Approximately 50 million people worldwide suffer from epilepsy. Chronic temporal lobe epilepsy (TLE) is one of the most prevalent forms of the syndrome. Currently this disorder is predominantly untreatable with medicines. It often occurs after a traumatic head injury (as, for example, that caused by a car accident) or fits induced by high fever. There is a delay (the so-called ‘latent period’) between the precipitating insult and the occurrence of spontaneous fits (seizures; defined as the onset of chronic TLE). It is during the latent period that changes in the brain leading to spontaneous fits occur. To obtain better treatment for chronic TLE, it is important to understand these changes. Ion channels are specialized proteins present in the membranes of brain nerve cells and are important for determining their function. Using models that replicate many if the features of the the human condition, I have recently shown that during the latent period, a particular ion channel, the h-channel, is persistently reduced in number in the cortex (an area of the brain where seizures are generated). I now wish to investigate more about the role of this channel in seizure generation. I also wish to understand more about how the expression of this channel is regulated in neurons. To do this, I am using a variety of state-of-the art techniques including recording electrical currents produced by activation of ion channels from single, genetically modified cortical nerve cells. The possible ramifications of this research are manifold, including a better understanding the mechanisms underlying TLE and the identification of novel treatment strategies.

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The introduction of antibacterial drugs into medical practice, which began in the 1930s and continued in spectacular fashion with the mass production of penicillin in the early 1940s gave rise to the belief that infectious diseases could be controlled and, eventually, mastered. However, the initial widespread optimism that antibiotics would banish serious infectious disease to the ?dustbin of history? has proven to be premature; infections remain the second leading cause of mortality worldwide and the major killer in the developing world. The reasons for the failure to defeat the threat from infection are many and complex but the emergence of antibiotic resistance has had an enormous impact on our ability to combat infection. Whenever a new antibiotic has been introduced, resistance has always followed. Bacteria have quickly found the means to counteract this threat to their survival and have developed ways to pass on their resistance genes to other bacteria. This acquired antibiotic resistance is responsible for the emergence of multi-resistant strains ? called ?superbugs? by the media ? that are now commonplace in hospitals and increasingly found in community acquired infections. Typical of these is MRSA, which has become a persistent and common permanent inhabitant of hospitals in the United Kingdom and elsewhere. While it is still sensitive to a few expensive antibiotics, there are well-founded fears that this may not last, in which case MRSA infections will become untreatable. We have been researching ways to reverse antibiotic resistance in MRSA, making it again sensitive to inexpensive antibiotics such as methicillin and oxacillin. These antibiotics prevent bacteria from making the rigid wall that they need to survive ? MRSA subverts this action by altering the way it makes its wall. We have found that a component of tea called ?ECg? interferes with the MRSA subverting machinery and converts the bacteria to methicillin sensitivity. Thus, ECg might be used in combination with oxacillin to restore antibiotic sensitivity. Unfortunately, ECg is rapidly broken down in the body but we have changed its chemical nature to make it resistant to breakdown and we have modified the compound in other ways to increase its attraction as a therapeutic. We now wish to understand better how ECg works against MRSA ? we know it inserts into the bacterial membrane - as deeper understanding of the processes involved will enable us to refine our most promising compounds and bring them closer to clinical use.